This invention relates to the transdermal delivery of nitroglycerin, in particular to transdermal delivery through the use of penetration enhancers.
Many drugs are destroyed on the first pass through the liver when taken orally. Because metabolism of said drugs is rapid, pharmacological activity and therapeutic effects of such drugs are not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems has met with increasing interest by researchers in the pharmaceutical drug delivery field.
Problems with efficacy arise, however, when using transdermal delivery systems. The device must supply a sufficient amount of the pharmaceutically active ingredient to the patient and a sufficient amount of drug must penetrate the patient's skin in order to obtain the desired pharmacological effect over a given period of time. Different means may be employed to obtain the desired efficacy over that period of time.
One means of attempting to increase the amount of drug delivered might be to include a higher concentration of the pharmaceutically active drug in the delivery system in the hope that by simply increasing the concentration of the drug, the amount of the drug penetrating the skin of the patient may be increased. However, this concept is limited by the amount of drug which can be administered through the skin, i.e., the skin acts as a rate-limitation means.
Another means for increasing the amount of drug administered and thereby obtaining the desired effect involves increasing the surface area contact of the delivery system with the skin. Although an increase in the surface area will increase the amount of drug delivered to the patient, there are, of course, practical limitations with respect to increasing this surface area. The cost of producing very large delivery systems is prohibitive and patients are unlikely to wear a delivery system which has a surface such that it covers a large portion of the skin.
A completely different concept for increasing transdermal delivery of a pharmaceutically active drug depends on the incorporation of one or more skin penetration enhancers in the drug delivery system. Use, however, of such enhancers is subject to certain limitations, for example penetration enhancers should be dermatologically acceptable and compatible with the pharmaceutically active drug as well as the delivery system into which it is incorporated.
Numerous patents and publications have disclosed that penetration enhancers are generally useful in delivering nitroglycerin transdermally. However, the penetration enhancers of the present invention are unexpectedly superior to those previously known.
U.S. Pat. No. 4,291,015 to Keith, et al., shows the general state of the transdermal delivery art, and in particular, discloses the use of a polymeric diffusion matrix for the sustained release of pharmaceutically active drugs. The matrix is covered by a backing layer and applied to the skin where diffusion of the drug occurs and the drug is transdermally delivered to the patient.
U.S. Pat. No. 4,409,206 discloses a related transdermal delivery system, wherein the drug is dispersed within an adhesive (see also U.S. Pat. No. 4,390,520). In accordance with this system, the drug is dispersed in a pressure-sensitive adhesive which adheres to the skin during use. The drug simply diffuses from the adhesive and is absorbed through the skin.
U.S. Pat. No. 4,751,087 discloses the use of butyl stearate, ethyl oleate and equivalent fatty acid esters containing 14 to 20 carbon atoms in combination with glyceryl monolaurate as penetration enhancers in the transdermal delivery of nitroglycerin.
European Patent Application 123,948 published on Nov. 7, 1984 discloses the use of 1-pyroglutamyloxy-2,3-dihydroxypropane as a penetration enhancer for the transdermal delivery of nitroglycerin.
U.S. Pat. No. 3,711,602 discloses the use of dimethyl sulfoxide (DMSO) as a penetration enhancer for numerous medicaments, one of which is nitroglycerin.
European Patent Application 179,277 published on Apr. 30, 1986 discloses the use of dialkyl phosphates as penetration enhancers for coronary vasodilators such as nitroglycerin.
European Patent Application 196,769 published on Oct. 8, 1986 discloses transdermal patches comprised of certain preferred silicone polymer matrices and an adhesive layer comprising a skin penetration enhancer. Certain particular penetration enhancers are disclosed as having slight penetration enhancing activity, but are indicated to be inferior to the numerous esters disclosed. No mention is made of in vivo blood levels achieved through the use of selected penetration enhancers.
British Patent Application no. 2,081,582A published on Feb. 24, 1982 discloses the use of a silicone polymeric backing layer in combination with a hydrophobic solvent system (e.g. mineral oil) to enhance nitroglycerin penetration.
PCT Application no. 86/02052 published on Apr. 9, 1987 (pub. No. W087/01935) discloses the use of 1-dodecanoyl hexahydro-1H-azepine as well as related compounds for transdermal penetration enhancement.
More recently, there have been teachings with respect to the use of oleic acid as a penetration enhancer. (See Cooper, Eugene, R., "Increased Skin Permeability for Lipophilic Molecules" Journal of Pharmaceutical Sciences, volume 73, number 8, August 1984.) Cooper discloses the use of oleic acid in different concentrations in the presence of propylene glycol as a solid. Oleic acid does appear to enhance penetration of the active ingredient salicylic acid. Cooper also discloses the use of oleic acid in combination with 1,2-butanediol. The article specifically indicates that "other diols also exhibit this synergism with lipids, but the effects are less pronounced as the chain length is increased". Cooper teaches that the treatment of the skin with surfactants can have a substantial influence on increasing the penetration of polar molecules. However, such surfactants do not generally increase the transdermal penetration of non-polar molecules. Accordingly, Cooper appears to teach only the use of small amounts of oleic acid either alone or in combination with diols of short chain length and contains no teachings with respect to the use of large amounts of oleic acid alone or in combination with long chain diols and actually teaches against the use of such long chain diols.
U.S. Pat. No. 4,305,936 discloses a solution for topical or local application comprised of a corticosteroid in a carrier. The carrier is comprised of 1 to 4% by weight of solubilizing agents of a glycerol ester of a fatty acid containing 6 to 22 carbon atoms, 10 to 50% by weight of an alkanol cosolvent and from 20 to 50% by weight of water. The patent also indicates that the carrier can include other "non-essential ingredients" such as a suitable auxiliary adjuvant in an amount of up to 10% by weight. Oleic acid is mentioned as a suitable auxiliary adjuvant. The patent does not appear to contain any teaching with respect to the effect oleic acid might have on enhancing penetration and does not appear to contain any teachings with respect to the use of large amounts of oleic acid alone or in combination with a long chain diol.
Oleic acid has been used as a vehicle in which salicylic acid and carbinoxamine have been incorporated. See "Percutaneous Absorption of Drugs From Oily Vehicles" Washitake, et al., Journal of Pharmaceutical Sciences, Vol. 64, No. 3, pages 397-401. Washitake, et al. demonstrate that the effect of oleic acid varies depending on the active ingredient. Therefore, it is not possible to accurately predict which pharmaceutically active compounds might have their skin penetration enhanced by the use of oleic acid.
U.S. Pat. No. 4,455,146 discloses a plaster comprised of a thermoplastic elastomer dissolved in an oil or higher fatty acid, a tack-providing resin and an active ingredient. The "higher fatty acid" may be present in the range of 25 to 370 parts by weight per 100 parts by weight of the thermoplastic elastomer. The active ingredient may be present in an amount in the range of 0.09 to 110 parts by weight per 100 parts by weight of the thermoplastic elastomer, (see column 4, lines 3-35). Oleic acid is mentioned as "one of the preferred" higher fatty acids, (see column 3, lines 16-17).
European Patent Application 43,738, published Jan. 13, 1982, discloses enhanced skin penetration of lipophilic compounds using binary vehicles containing a C.sub.3 -C.sub.4 diol, diol ester or diol ether (including butanediol) and a cell-envelope disrupting compound, e.g., a compound R.sup.3 -X wherein R.sup.3 can be a non-terminal alkenyl of 7-22 carbons and X.dbd.OH (such as oleic, linoleic or linolenic acid).
PCT Publication No. 87/03490, published Jun. 18, 1987, discloses transdermal delivery of drugs using as a penetration enhancer 2-ethyl-1,3-hexanediol and/or oleic acid, wherein the preferred concentration of oleic acid is 5%.
U.S. Pat. No. 4,537,776 discloses the transdermal delivery of drugs using a combination of a) N-methyl-pyrrolidone, pyrrolidone or N-(2-hydroxyethyl)pyrrolidone, preferably the latter, and b) a cell-envelope disordering compound such as oleic acid or oleyl alcohol, wherein the ratio of a to b is 1:5 to 500:1.
U.S. Pat. No. 4,557,934 discloses a penetration-enhancing vehicle comprised of 1-dodecyl-azacycloheptan-2-one (i.e., Azone.RTM., commercially available from Nelson Research and Development, Co., Irvine, Calif.) in combination with a C.sub.3 -C.sub.4 diol or an N-substituted azacycloalkyl-2-one such as N-methyl-2-pyrrolidone.
European Patent Application 267,617, published May 18, 1988, discloses penetration-enhancing vehicles comprising a combination of a lower alkanol, e.g. ethanol, and a cell-envelope disordering compound such as oleic acid or oleyl alcohol.
U.S. Pat. No. 4,322,433 discloses a sustained release biphasic cream carrier suitable for nitroglycerin. The components include a C.sub.8 -C.sub.18 aliphatic alcohol and a hydrophilic component, e.g. water or propylene glycol, in a ratio which provides a specific hydrophilic/lipophilic balance value.
Although some percutaneous penetration enhancers are known, there remains a need for an enhancer which significantly increases the rate of transdermal delivery of a pharmacologically active drug to a patient.
Other types of transdermal delivery systems are known and each has its various advantages and disadvantages with respect to the transdermal delivery of different types of pharmaceutically active drugs. None of the conventional formulations provide the flux seen with the present invention, wherein in vitro results show about a two-fold increase and the in vivo results show about a four-fold increase in penetration over commercial transdermal nitroglycerin formulations.